tbuckley/cabot-search huggingface dataset:
Abstract 6227: An optimized preclinical antibody-drug conjugate against cancers with cKIT overexpression or activating mutations
Authors: Jin-Ock Kim, Han-Jik Ko, Jae-Won Kim, Sang Gyu Park
Journal: Cancer Research (2022)

Abstract cKIT overexpression and activating mutations have been observed in many types of cancer, including small cell lung cancer (SCLC), gastrointestinal stromal tumor (GIST), and acute myeloid leukemia (AML), and are known to be predictive of poor prognosis. In previously reported work, NN2101-DM1, a fully human, anti-cKIT antibody-drug conjugate (ADC), was developed as a proof-of-concept (PoC) entity by conjugating the site-nonspecific and uncleavable linker SMCC with the microtubule inhibitory payload DM1. This linker-payload system is the same used in ado-trastuzumab emtansine, an approved ADC for HER2-positive breast cancer. NN2101-DM1 showed therapeutic efficacy against SCLC and GIST both in vitro and in xenograft models in vivo, demonstrating the feasibility of ADC development using NN2101. Despite the potent efficacy of NN2101-DM1, there are inherent limitations to SMCC linker and DM1 payload systems. The nonspecific attachment of the linker to the antibody produces highly heterogeneous drug-antibody ratios (DARs) with unpredictable attachment. Additionally, impaired lysosomal proteolytic activity has been shown to contribute to resistance to SMCC-DM1 cleavage. To optimize the ADC configuration for advancement to a clinical candidate, four types of ADC with different linker-payload combinations and DARs were designed, and their efficacy and safety were evaluated in vitro and in vivo. Among them, NN3201, a conjugation of the antimitotic payload MMAE to the cKIT-targeting antibody NN2101 via a site-specific, cleavable peptide linker, with a homogenous (&amp;gt;95%) DAR of 4 was selected as a lead candidate. This linker system utilizes a cysteine re-bridging technology to produce site-specific conjugation with high DAR homogeneity. NN3201 showed consistent sub-nanomolar IC50s in several in vitro cell lines and demonstrated complete remission as monotherapy in SCLC (H526), GIST (GIST-T1), AML (Kasumi-1), and mastocytoma (HMC 1.2) cell-derived xenograft models in doses ranging from 1.0-3.0 mg/kg. There were no significant toxicities detected at doses up to 60 mg/kg in normal mice, suggesting a therapeutic index greater than 20 times. In conclusion, NN3201 showed potent anti-tumor activity and was selected as preclinical candidate. Citation Format: Jin-Ock Kim, Han-Jik Ko, Jae-Won Kim, Sang Gyu Park. An optimized preclinical antibody-drug conjugate against cancers with cKIT overexpression or activating mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6227.
Abstract 2073: Childhood vaccine-specific CD4+T cell recall coordinates antitumor type I and II immunity
Authors: Michael Clavon Brown, Zachary P. Mckay, Yuanfan Yang, Darell D. Bigner, Smita K. Nair, Matthias Gromeier
Journal: Cancer Research (2022)

Abstract A recombinant poliovirus (rPV) derived from the live-attenuated Sabin oral polio vaccine strain, is being tested in multi-institutional phase II clinical trials for recurrent glioblastoma (NCT04479241); unresectable, anti-PD-1 refractory melanoma (NCT04577807); and bladder cancer and head and neck squamous cell carcinomas (NCT04690699) in combination with PD-1/PD-L1 blockade. rPV capsid is identical to that of childhood polio vaccines, against which public health mandated vaccination is near universal. In non-vaccinated mice, rPV mediates antitumor efficacy in a replication-dependent manner via engaging innate inflammation and antitumor T cells. Accordingly, it was anticipated that pre-existing immunity to rPV impedes antitumor therapy. Strikingly, despite curtailing intratumor viral replication, prior polio vaccination in mice substantially bolstered the antitumor efficacy of rPV relative to mice vaccinated with a control antigen (KLH). Intratumor recall responses induced by polio and tetanus antigens also delayed tumor growth. Recall antigen therapy was associated with marked intratumor influx of eosinophils, PD1 and Granzyme B expressing type 2 innate lymphoid cells (ILC2s), conventional CD4+ T cells, and increased expression of IFN-γ, TNF, and Granzyme B in tumor infiltrating T cells. The antitumor efficacy of polio recall antigen was mediated by CD4+ T cells, partially depended upon both CD8+ T cells and eosinophils, and was independent of B cells. Intratumor polio and tetanus recall antigen therapy bolstered the antitumor function of tumor-specific OT-I CD8+ T cells, indicating that intratumor CD4+ T cell recall provides help to antitumor CD8+ T cells. Recall antigen therapy complemented antitumor effects of immune checkpoint blockade and innate stimulating immunotherapy. This work reveals that childhood vaccine-specific CD4+ T cells hold cancer immunotherapy potential and represent a novel mechanism to simultaneously engage both type I and II antitumor immunity. Citation Format: Michael Clavon Brown, Zachary P. Mckay, Yuanfan Yang, Darell D. Bigner, Smita K. Nair, Matthias Gromeier. Childhood vaccine-specific CD4+T cell recall coordinates antitumor type I and II immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2073.
Abstract LB041: Differential response to progranulin in proliferative and metastatic SW13 cell subtypes
Authors: Chika Okonya, McKale R. Montgomery, Agnes S. Pascual, Chandana Uppalapati, Kathryn J. Leyva, Elizabeth E. Hull
Journal: Cancer Research (2022)

Abstract The SW13 human adrenocortical carcinoma line exists in proliferative SW13- and metastatic SW13+ subtypes which interconvert by epigenetic mechanisms in an epithelial to mesenchymal transition (EMT) process. This work investigates the contribution of progranulin to the maintenance of and conversion between the SW13 subtypes. A prognostic biomarker in cancer, progranulin is a pleotropic signaling molecule composed of 7 highly conserved granulin repeats. Each granulin unit has independent and sometimes opposing activity in the regulation of diverse cellular activities including proliferation, chemoresistance, lysosomal function, migration, wound healing, and inflammation. Thus, the ultimate biological activity of progranulin is context-dependent as it relies on the expression of diverse intracellular and extracellular proteases. Treatment with exogenous progranulin increases growth of SW13- cells but not SW13+ cells, a finding which suggests differential processing. As the metastatic SW13+ subtype produces more progranulin than the SW13- subtype, these data are consistent with an inability of SW13+ to process endogenous progranulin to the mitogenic granulin unit(s). Immunoblotting with antibodies specific for granulin repeats indicates that progranulin is processed differently in each subtype. In this work, we focused on lysosomes as a potential site for differential processing of progranulin for several reasons. First, lysosomes play a role in EMT. Second, lysosomal proteases have been shown to process progranulin and progranulin itself plays a role in lysosome maturation. Finally, preliminary data suggest that there are differences in lysosomal function and pH between the two subtypes. Ongoing experiments address the benefits of lysosomal acidification and the role that differential processing of progranulin may play on the maintenance and interconversion of the SW13 subtypes. Citation Format: Chika Okonya, McKale R. Montgomery, Agnes S. Pascual, Chandana Uppalapati, Kathryn J. Leyva, Elizabeth E. Hull. Differential response to progranulin in proliferative and metastatic SW13 cell subtypes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr LB041.
Abstract 3987: Brain penetrant HDAC and PI3K/mTOR inhibitors synergize to induce DIPG cell death
Authors: Katherine Barnett, Hyuk Jean Kwon, Orlandi Novak, Charles Eberhart, Eric Raabe
Journal: Cancer Research (2022)

Abstract Diffuse intrinsic pontine glioma (DIPG) is a universally fatal pediatric brain tumor. We have previously shown that the brain penetrant class 1 HDAC inhibitor RG2833 (RGFP109) inhibits cell growth (MTS assay for HSJD007 p=0.0004, JHH-DIPG1 p=0.001, SF-7761 p=0.04, SU-DIPG13 p=0.01 by t-test), reduces proliferation (phospho-Rb Western blot, BrdU immunofluorescence HSJD007 p=0.008, JHH-DIPG1 p=0.0002 by t-test), and induces apoptosis (cPARP Western blot, cleaved caspase 3 immunofluorescence HSJD007 p&amp;lt;0.003, JHH-DIPG1 p=0.0026 by t-test) in multiple DIPG cell lines. We have also shown that treatment of a DIPG flank tumor mouse model with RG2833 alone for 1 week suppresses flank tumor growth (p&amp;lt; 0.005 by t-test) and induces apoptosis (Western blot for cPARP). In a DIPG orthotopic mouse model, we confirmed that RG2833 100mg/kg has on target activity in the mouse brain (Western blot for histone 3 acetylation) without causing toxicity. We next sought to identify a rational combination therapy to enhance RG2833 efficacy against DIPG. We found that RG2833 increases expression of negative cell cycle regulators p16, p21, and p27 and decreases expression of anti-apoptotic proteins BCL-2, BCL-XL, and XIAP (assessed by Western blot). Given that PI3K/mTOR pathway is upregulated in DIPG and plays an important role in cell cycle regulation via p21 and the FOXO signaling, we hypothesized that RG2833 would synergize with inhibitors of PI3K/mTOR. The brain penetrant PI3K/mTOR inhibitor Paxalisib is currently being evaluated in a phase 1 clinical trial of children with DIPG. We found that RG2833 has strong synergism with Paxalisib at clinically achievable doses (Loewe synergy scores by SynergyFinder for SF7761 and JHH-DIPG1 &amp;gt;20). Evaluation of combination treatment for apoptotic effects in vitro and in vivo are ongoing. These findings identify RG2833 and Paxalisib as a promising combination therapy for DIPG. Citation Format: Katherine Barnett, Hyuk Jean Kwon, Orlandi Novak, Charles Eberhart, Eric Raabe. Brain penetrant HDAC and PI3K/mTOR inhibitors synergize to induce DIPG cell death [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3987.
Abstract 1289: Systemic immune response of prostate cancer patients to alpha-emitting radiotherapy
Authors: Sapna Lunj, Hitesh Mistry, YeePei Song, Kamlesh Patel, Hannah Nightingale, Tim Smith, Peter Hoskin, Catharine West, Ananya Choudhury
Journal: Cancer Research (2022)

Abstract Targeted alpha therapy (TAT) is a type of radiotherapy (RT) that uses alpha-emitting radionuclides. These radionuclides have a natural affinity for areas of bone metastases (i.e., radium-223, Ra-223) or can label specific tumour targets (i.e., prostate-specific membrane antigen). Conventional photon irradiation (i.e., external beam) can activate or suppress immune responses. The resulting immune response is dictated by the release of soluble markers such as cytokines (i.e., IL-6) and damage associated molecular patterns, DAMPs (calreticulin). Less is known about the immune response induced by alpha-emitters. With increased interest in using TAT for cancer patients, it is important to gain a more in depth knowledge regarding the immune response of alpha emitters. Aim: Explore the systemic immune response of prostate cancer (PCa) patients to alpha-emitting RT by studying circulating cytokines, checkpoint molecules, matrix metalloproteinases (MMPs) and DAMPs. Methods: The cohort comprised of 43 patients with metastatic castration-resistant PCa treated with up to six four-weekly injections of the alpha emitter, Ra-223. We measured longitudinal changes in 61 plasma markers using the Luminex assay. The plasma markers included cytokines, checkpoint molecules and DAMPs. Results: Ra-223 induced longitudinal changes in 14 plasma markers over the course of treatment (T2-T6) compared with pre-treatment levels (T1). Most of the observed RT-induced changes occurred after four injections of Ra-223 (T5), where 9 of the 14 plasma markers changed significantly. The table summarises T5 findings (presented as mean concentration, pg/ml; statistical analysis using Wilcoxon matched-pairs signed rank test). Conclusion: Our data demonstrates that alpha-emitting RT induces systemic immune responses that can be measured in the plasma of patients. Given the diverse role of these markers, further study is needed to explore the biological implications of these systemic changes on patient outcome. Changes in plasma markers in patients treated with Ra-223 T1 T5 P value IL-8 6.7±0.9 9.7±1.3 0.0009 IL-2R 293.5±42.9 364.5±69.7 0.0247 IP-10 18.4±2.3 21.8±2.5 0.0243 RANTES 2668.8±173.4 2944.7±164.6 0.0455 BTLA 549.9±153.5 527.7±265.2 0.0319 CD137 49.6±8.9 39.1±13.5 0.0099 Calreticulin 7868±3514.9 9238.4±808.5 0.0386 RAGE 63.9±4.7 52.3±5.1 0.0014 MMP1 66.1±7.5 84.9±12.6 0.0245 Citation Format: Sapna Lunj, Hitesh Mistry, YeePei Song, Kamlesh Patel, Hannah Nightingale, Tim Smith, Peter Hoskin, Catharine West, Ananya Choudhury. Systemic immune response of prostate cancer patients to alpha-emitting radiotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1289.
Abstract 4010: Analytical concordance of 3 independent diagnostic assays for the detection of <i>FGFR</i> alterations in urothelial carcinoma tumor tissue
Authors: Christopher Major, Songbai Wang
Journal: Cancer Research (2022)

Abstract Background: The Qiagen therascreen® companion diagnostic is FDA approved to aid identifying patients with urothelial carcinoma who harbor susceptible fibroblast growth factor receptor (FGFR) gene alterations and are therefore eligible for treatment with erdafitinib, an FGFR inhibitor. We examined analytical concordance between the Qiagen assay against 2 next-generation sequencing (NGS) platforms used to identify molecular targets for tailored treatment, including FGFR alterations. Methods: Formalin-fixed paraffin-embedded tumor tissue samples (N = 54: muscle-invasive bladder cancer [n = 18], non-muscle-invasive bladder cancer [n = 23], cholangiocarcinoma [n = 12], non-small-cell lung cancer [n = 1]) were obtained commercially. FGFR alterations were detected using the Qiagen therascreen FGFR RGQ RT-PCR Kit and tested for concordance vs NGS platforms from Thermo Fisher Scientific (Oncomine Comprehensive™ assay) and Illumina (TruSight™ Oncology 500 [TSO500]). Concordance assessment of positive, negative, and overall agreement was done. Results: 54 samples yielded valid results using the Qiagen assay. 51 met quality control metrics with the Thermo Fisher assay, and 47 with the Illumina assay. FGFR alterations were found in 17 samples, including 16 with single nucleotide variants (SNVs): R248C (n = 1), S249C (n = 7), and Y373C (n = 8), 1 with an FGFR3:TACC3 fusion and 1 with both FGFR3:TACC3 fusion and S249C mutation. Qualitative positive agreement (100%), negative agreement (100%), and overall agreement (100%) between the Thermo Fisher NGS assay and the Illumina NGS assay vs the Qiagen assay for SNVs was observed (Table). 2 fusions detected as positive by the Qiagen assay were not identified as the TACC3v1 fusion by NGS assays. Conclusions: There was a high level of analytical concordance in detection of FGFR alterations indicated for erdafitinib between the Qiagen companion diagnostic assay and 2 commercially available NGS platforms. Table. Concordance in detection of FGFR alterations Qiagen therascreen RT-PCR Positive Negative NGS Thermo Fisher Oncomine Dx Positive 17/17 (100%); 95% CI, 86.3%-100% 0/34 (0) Negative 0/17 (0) 34/34 (100%); 95% CI, 92.6%-100% Overall 51/51 (100%); 95% CI, 95.0%-100% NGS Illumina TSO500 Positive 17/17 (100%); 95% CI, 86.3%-100% 0/30 (0) Negative 0/17 (0) 30/30 (100%); 95% CI, 91.7%-100% Overall 47/47 (100%); 95% CI, 94.6%-100% Citation Format: Christopher Major, Songbai Wang. Analytical concordance of 3 independent diagnostic assays for the detection of FGFR alterations in urothelial carcinoma tumor tissue [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4010.
Integrated genomic analyses of acral and mucosal melanomas nominate novel driver genes
Authors: Meng Wang, Ishani Banik, A. Hunter Shain, Iwei Yeh, Boris C. Bastian
Journal: Genome Medicine (2022)

Abstract Background Acral and mucosal melanomas are aggressive subtypes of melanoma, which have a significantly lower burden of somatic mutations than cutaneous melanomas, but more frequent copy number variations, focused gene amplifications, and structural alterations. The landscapes of their genomic alterations remain to be fully characterized. Methods We compiled sequencing data of 240 human acral and mucosal melanoma samples from 11 previously published studies and applied a uniform pipeline to call tumor cell content, ploidy, somatic and germline mutations, as well as CNVs, LOH, and SVs. We identified genes that are significantly mutated or recurrently affected by CNVs and implicated in oncogenesis. We further examined the difference in the frequency of recurrent pathogenic alterations between the two melanoma subtypes, correlation between pathogenic alterations, and their association with clinical features. Results We nominated PTPRJ , mutated and homozygously deleted in 3.8% (9/240) and 0.8% (2/240) of samples, respectively, as a probable tumor suppressor gene, and FER and SKP2 , amplified in 3.8% and 11.7% of samples, respectively, as probable oncogenes. We further identified a long tail of infrequent pathogenic alterations, involving genes such as CIC and LZTR1 . Pathogenic germline mutations were observed on MITF , PTEN , ATM , and PRKN . We found BRAF V600E mutations in acral melanomas with fewer structural variations, suggesting that they are distinct and related to cutaneous melanomas. Amplifications of PAK1 and GAB2 were more commonly observed in acral melanomas, whereas SF3B1 R625 codon mutations were unique to mucosal melanomas (12.9%). Amplifications at 11q13-14 were frequently accompanied by fusion to a region on chromosome 6q12, revealing a recurrent novel structural rearrangement whose role remains to be elucidated. Conclusions Our meta-analysis expands the catalog of driver mutations in acral and mucosal melanomas, sheds new light on their pathogenesis and broadens the catalog of therapeutic targets for these difficult-to-treat cancers.
Abstract 5789: Multi-omic artificial intelligence outcome modeling of ovarian cancer, phase I: Whole exome and whole transcriptome data
Authors: Brian Orr, Robert P. Edwards, Mackenzy Radolec
Journal: Cancer Research (2022)

Abstract Background: Over a decade ago, the Cancer Genome Atlas (TCGA) provided the initial genomic characterization of ovarian cancer with targeted exome capture and sequencing. Unlike other TCGA analysis, they were unable to identify prognostic mutational profiles outside of BRCA status. There has been limited characterization of the ovarian cancer genomic profile since. Our objective presented here was to perform whole exome and whole transcriptome analysis of 241 ovarian cancer samples and compare to the TCGA dataset. This is the first phase of a muti-step ongoing analysis wherein we will input and correlate the complete genomic profile, complete patient outcome data, and immunohistochemical staining into a multi-omic artificial intelligence (AI) machine learning model with the aim of improved individualized outcome prediction. Methods: Tumor samples from 2000-2016 were obtained at time of surgery under approved University of Pittsburgh approved IRB consent. Whole exome and whole transcriptome sequencing were performed in collaboration with Helomics Corporation. Sequencing analysis was compared to TCGA data. Results: 241 patient samples underwent sequencing analysis. Similar to TCGA, most mutations were missense. I am having a difficulty interpreting the magee vs tcga comparison graphs, how to discuss the TP53 and BRCA comparison without using the lollipop charts and highlighting the rna-seq data into written form. Please add. Conclusions: We present our findings of one of the largest molecular characterizations of ovarian cancer. Similar to the TCGA, there is noted heterogeneity to the genomic profile of ovarian cancer. Multi-omic AI outcome modeling has the potential to overcome the gap defining prognostic sub-groups so that we can tailor therapies to the individual Citation Format: Brian Orr, Robert P. Edwards, Mackenzy Radolec. Multi-omic artificial intelligence outcome modeling of ovarian cancer, phase I: Whole exome and whole transcriptome data [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5789.
Abstract 671: Cryo-electronmicroscopy of PI3K reveals additional regulatory features
Authors: Jonathan R. Hart, Su Yang, Xiao Liu, Yingna Xu, Xinyu Zou, Huibing Zhang, Qingtong Zhou, Tian Xia, Yan Zhang, Dehua Yang, Ming-Wei Wang, Peter K. Vogt
Journal: Cancer Research (2022)

Abstract Many solid tumors have alterations in phosphoinositide 3-kinase (PI3K) signaling. These can occur through mutation of the p110alpha and p85alpha proteins of PI3Kalpha itself as well as through alterations to upstream receptor tyrosine kinases (RTKs) and phosphatases of PIP3, including PTEN. As a whole, PI3K signaling is one of the most frequently altered in cancer. These mutations lead to activation of the PI3K complex and to constitutive downstream signaling. This signaling allows cells to enter a pro-growth and pro-survival state which is beneficial to the cancer cells. The structure of PI3K has been extensively studied by crystallography and NMR. Here, we present our work on the full-length complex of p110alpha with p85alpha using cryo-EM. When compared with the previous structural studies, cryo-EM shows a similar structure and major structural features are unchanged. However, our cryo-EM studies revealed several additional structural features of the PI3K complex. Cryo-EM showed that SH3, BH and cSH2 domains of p85alpha can bind to p110alpha. When inhibited with Alpelisib, these domains form a stable cover of the active site of the kinase. These domains interact with the helical and kinase domains of p110alpha and the iSH2 domain of p85alpha. The position of these domains restricts access to the kinase active site and may contribute to the inhibition of PI3K activity by Alpelisib. When the PI3K complex binds to phosphorylated RTKs, the nSH2 binds to phosphotyrosine and relieves inhibitory interactions with the helical domain of p110alpha. Using cryo-EM, we have studied this activation by incubating the full-length PI3K complex with synthetic phosphopeptides. 2D cryo-EM class averages showed a dramatic rearrangement of the PI3K complex. In addition to the expected displacement of the nSH2 domain, the ABD and iSH2 domains undergo structural changes. Acknowledgments: This work was supported by the National Cancer Institute of the National Institutes of Health under awards R35 CA197582 (PKV) and R50 CA243899 (JRH). Citation Format: Jonathan R. Hart, Su Yang, Xiao Liu, Yingna Xu, Xinyu Zou, Huibing Zhang, Qingtong Zhou, Tian Xia, Yan Zhang, Dehua Yang, Ming-Wei Wang, Peter K. Vogt. Cryo-electronmicroscopy of PI3K reveals additional regulatory features [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 671.